Acute Depletion of Endothelial beta 3-Integrin Transiently Inhibits Tumor Growth and Angiogenesis in Mice

作者：Steri Veronica; Ellison Tim S; Gontarczyk Aleksander Maksym; Weilbaecher Katherine; Schneider Jochen G; Edwards Dylan; Fruttiger Marcus; Hodivala Dilke Kairbaan M; Robinson Stephen Douglas^*

来源：Circulation Research, 2014, 114(1): 79-91.

DOI：10.1161/CIRCRESAHA.114.301591

• angiogenesis inhibitors
• endothelium
• integrin V3
• neoplasms

Rationale: The dramatic upregulation of v3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against v3-integrin that are currently in clinical trials. In 2002, we reported that 3-integrin-knockout mice exhibit enhanced tumor growth and angiogenesis. However, as 3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of 3-integrin function. %26lt;br%26gt;Objective: Our aim was to examine the endothelial-specific contribution 3-integrin makes to tumor growth and angiogenesis. %26lt;br%26gt;Methods and Results: We have crossed 3-integrin-floxed (3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial 3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial 3-integrin expression. %26lt;br%26gt;Conclusions: Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of 3-integrin to inhibit tumor growth and angiogenesis.

• 出版日期2014-1-3